FDA advisory committee on MDMA, 2024

Questions to the Committee and Discussion (pp. 340–343)

DR. NARENDRAN: Thank you. The committee will now turn its attention to address the task at hand, the careful consideration of the data before the committee, as well as the public comments. We will now proceed with the questions to the committee and panel discussions. I would like to remind public observers that while the meeting is open for public observation, public attendees may not participate, except at the specific request of the panel. After I read each question, we will pause for any questions or comments concerning the [p. 341] wording of the question. We will proceed with our first question, which is a discussion question. Question number 1, discuss the evidence of effectiveness for midomafetamine for the following treatment of posttraumatic stress disorder. Consider the following: the potential impact of functional unblinding on interpretability of efficacy results; the durability of effect; the role of psychological intervention in the treatment paradigm. Are there any questions about the question? Dr. Dunn?

DR. DUNN: Walter Dunn, UCLA. For the agency, we see discuss the evidence of the effectiveness of midomafetamine, so do you mean the drug plus the proposed psychotherapy and not just the drug alone?

DR. FARCHIONE: This is Tiffany Farchione. I think it's fair to comment on either.

DR. NARENDRAN: Any other questions about the question?

(No response.)

[p. 342]

DR. NARENDRAN: Okay. Does anybody want to go first? Dr. Dunn? Thank you.

DR. DUNN: Walter Dunn, UCLA, VA. Regarding the first question about the potential impact of functional unblinding, as was mentioned previously, this is a known issue with medications such as MDMA and other classical psychedelics. I think it does degrade my confidence in the efficacy results a bit, even perhaps some of the safety issues. The main concern for me is the functional unblinding, with the expectational bias, with potential misconduct. I think if you line up all those three things together, that is the major issue for me. So regarding misconduct, it sounds like the agency is investigating that, so I trust that they'll do a thorough job on it. Unfortunately, for the expectation bias, we don't have any data on that. As my colleague, Fiedorowicz, alluded to earlier when he asked about that, this was not data that was obtained during the trial, so we don't know the expectation bias of [p. 343] the subjects, of the therapists, or even actually the independent raters. So perhaps this is something that, for future psychedelic trials, maybe the agency wants to consider, as I think that would play a role, especially in its interaction with the functional unblinding aspect of it and interpreting the efficacy results. That's my comment on that.

[Discussion of questions 1–4, pp. 343–412, omitted.]

Voting questions 5 and 6 (pp. 412–425)

DR. NARENDRAN: We'll be using an electronic [p. 413] voting system for this meeting, so once we begin the vote, the buttons will start flashing and will continue to flash even after you've entered your vote. Please press the button firmly that corresponds to your vote. If you're unsure of your vote or you wish to change your vote, you may press the corresponding button until the vote is closed. After everyone has completed their vote, the vote will be locked in. The vote will then be displayed on the screen. The DFO will read the vote from the screen into the record. Next, we will go around the room, and each individual who voted will state their name and vote into the record. You can also state the reason why you voted as you did, if you want to. We will continue in the same manner until all questions have been answered or discussed. The virtual people will be voting through e-mail to the DFO. Question number 5, do the available data show that the drug is effective in patients with posttraumatic stress disorder? Vote. [p. 414] (Voting.)

DR. FRIMPONG: There are 2 yeses and 9 noes, no abstentions.

DR. NARENDRAN: Now that the vote is complete, we will go around the table and have everyone who voted state their name, vote, and if you want to, you can state the reason why you voted into the record. We'll start with Dr. Dunn.

DR. DUNN: Walter Dunn, UCLA Greater Los Angeles, VA. My vote was yes. I think there are concerns about the functional unblinding in addition to the expectation bias, potentially reducing my confidence in the effect sizes that were reported; however, I can't overlook the fact that the effect sizes were fairly large, and I think worst case scenario would be down to something like 0.3, 0.4. But per Dr. Buracchio's guidance earlier, and really not taking into consideration the possibility for misconduct, I think if that is fully fleshed out, and if that really changes the data, based off of some type of sensitivity [p. 415] analysis where sites that were identified to have engaged in misconduct were removed from the efficacy analysis, then I think we should see that data. But again, assuming that no misconduct occurred, but accepting that there was functional blinding and most likely expectational bias, I think that the defect sizes are still large enough that this treatment, drug plus psychotherapy, can be effective for patients with posttraumatic stress disorder. Thank you.

DR. NARENDRAN: Raj Narendran, and I voted no. I felt the functional unblinding, lack of management of expectation bias, and also the selection bias of people, 40 percent of them had used MDMA. So not without accounting for what their expectation was, and somehow incorporating that into some kind of statistical model, I think it's meaningless. I just feel very convinced that I had to vote no.

DR. FIEDOROWICZ: Jess Fiedorowicz. I voted no, and nothing to add to the discussion.

DR. IYENGAR: Satish Iyengar. I also voted [p. 416] no for similar reasons that Raj mentioned. It actually felt strange to vote no when the p-value started with three zeros, but there were just too many problems with it, and unless you have a model for the biases, it's really hard to make a judgment about whether it's accounted for.

MS. WITCZAK: Kim Witczak, consumer rep. I voted no. I do think there is potential for this, but based on selection bias, functional unblinding, it didn't feel right, and the potential for some misconduct and manipulating the trial results.

MS. JONIAK-GRANT: Elizabeth Joniak-Grant. I voted no. This was a difficult decision for me. I think that some of the data was promising, but given the 40 percent that had previously used MDMA, limited information about recruitment and recruitment coming through referrals, I really wonder how much that impacted the efficacy. Durability not being assessed multiple times and a one-shot deal was another issue for me, and I am concerned with the lack of diversity in the sample and what that would mean for the general [p. 417] population.

DR. HERTIG: John Hertig. I'm the second of the two that voted yes. Along with Dr. Dunn, I do share his assessment, and in the interest of time don't have much additional to share. I do believe that the therapy holds clinical promise. Thank you.

DR. AMIRSHAHI: Maryann Amirshahi. I voted no. Similar to many of my colleagues, I felt that the large positive effect was denuded by the significant confounders. Although I do believe that there was a signal, it just needs to be better studied. Additionally, the population considerations that we discussed really limit the generalizability to the larger PTSD population; and then also, the inability to tease out the relative effect of the variable therapy provided. Thank you.

DR. REBO: Elizabeth Rebo. I voted no, very similar to concerns that Maryann just articulated.

DR. NARENDRAN: I do want to give our virtual members an opportunity?

[p. 418]

Dr. Barone?

DR. BARONE: Hi. Melissa Barone. I voted no. In the interest of time, my concerns have already been noted by the committee.

DR. NARENDRAN: Dr. Holtzheimer?

DR. HOLTZHEIMER: Paul Holtzheimer, National Center for PTSD. I also voted no for reasons previously stated.

DR. NARENDRAN: We'll now proceed to question 6, which is another voting question, and same instructions. We'll be using the electronic voting system. Once we begin the vote, the buttons will start flashing, and will continue to flash even after you entered the vote. Please press the button firmly that corresponds to your vote. The DFO will read the vote from the screen into the record, and then we'll go around the room, and each individual who voted will state their name and why they voted, if they wish to. Question number 6, do the benefits of midomafetamine with FDA's proposed risk evaluation and mitigation strategy, REMS, outweigh its risks [p. 419] for the treatment of patients with PTSD? Any questions about the question?

(No response.)

DR. NARENDRAN: No question about the question, and we can vote.

(Vote.)

DR. FRIMPONG: Bear with us. We're still waiting for one more vote from one of our virtual panel members.

(Pause.)

DR. FRIMPONG: For our question, there is 1 vote for yes and 10 votes for no, and no abstentions.

DR. NARENDRAN: We’ll start from this side of the table. Dr. Rebo?

DR. REBO: Elizabeth Rebo. I said no, primarily because there are too many missing parameters around it for me to feel comfortable saying yes.

DR. AMIRSHAHI: Maryann Amirshahi. I also said no for the fact that there was a lot of [p. 420] missing safety data, and the efficacy data is somewhat equivocal in my mind. Thank you.

DR. HERTIG: John Hertig. I also said no. Although I did feel there was some effectiveness here, I don't feel like the risks, the missing data, the gaps, the unknowns outweigh that benefit, so I voted no. Thank you.

DR. JONIAK-GRANT: Elizabeth Joniak-Grant. I voted no. Sorry. It's been a long day. I think we're still trying to understand the risks and echoing what others have said before. So for me, it's a no.

MS. WITCZAK: Kim Witczak, consumer rep. I voted no, and because we are in this new territory, I want to commend both the FDA and the sponsor for bringing this forward. I don't think we're quite there yet, but I think the conversation's there, and I'm looking forward to seeing where it can go. But for the reasons that we've proceeded to talk about, I voted no.

DR. IYENGAR: Satish Iyengar from Pittsburgh. I also voted no for pretty much the [p. 421] same reasons as my colleagues.

DR. FIEDOROWICZ: Jess Fiedorowicz. I voted no.

DR. NARENDRAN: Raj Narendran, and I voted no.

DR. DUNN: Walter Dunn. I voted yes; not the first time I've been on the short end of a vote, and perhaps this requires a little bit of commentary. I wish we had a Likert scale in addition to our yes and no votes because I voted yes, however low on my confidence about the risk-benefit. Two things about it; number one, I think the greatest strength of the treatment is also its greatest liability, and that's the therapists in the room, the psychotherapy, and, unfortunately, that sounds like it's out of the direct purview of the agency. Number two, as was mentioned previously, the REMS is still something that the sponsor is having conversations with the agency, so we actually don't know what that REMS looks like; however, based off of what's been presented thus [p. 422] far, it's probably 75 percent of the way there. You're definitely on the right track. I think a tweak here and there can address some the safety concerns we've brought up. So those are some of the things that would shift me towards the no vote. Ultimately, I voted yes because I'm putting on my clinician hat, and as has been stated before, we are in dire need of new treatments for PTSD. And I'm especially sympathetic to the stories of our veterans that were here during the public commentary. Working in the VA, as a former service member myself, I have colleagues who deployed and have PTSD, and this has the potential to make a difference. Now, that's not without its risks, but as I like to tell all my trainees, there's no free lunch in medicine, and what has the potential for benefit has the potential for harm. So again, as has been mentioned by the agency multiple times, there's no such thing as a, quote/unquote, "safe treatment." It's all about the risk-benefit profile. So I think as the REMS evolves, I think it can be made a [p. 423] safer treatment in the right clinical context, in the right healthcare settings, so I think that advantage can be gained with the right guardrails in place. Thank you.

DR. NARENDRAN: We'll go to our virtual panel members. Dr. Holtzheimer?

DR. HOLTZHEIMER: Paul Holtzheimer, National Center for PTSD. I voted no, largely for reasons stated. I'll just comment that I absolutely agree that we need new and better treatments for PTSD, especially in the somatic treatment space; however, I also note that premature introduction of a treatment can actually stifle development, and stifle implementation, and lead to premature adoption of treatments that are either not completely known to be safe, not fully effective, or not being used at their optimal efficacy. I think this is a really exciting treatment. I'm really encouraged by the results to date, but I feel that both from an efficacy and a safety standpoint, it is still premature.

[p. 424]

DR. NARENDRAN: Dr. Barone?

DR. BARONE: Melissa Barone. I voted no. I think that this treatment is incredibly promising and has a lot of potential to help a lot of patients. I just think that there needs to be more research done to address some of the questions and concerns that have been brought up today. Thank you.

DR. NARENDRAN: Okay. I do want to thank the sponsor for really trying to bring this novel therapeutic and putting all the effort to get this in front of the agency. I do want to thank the agency for the very difficult problems you guys deal with and have to contend with psychedelics as a therapeutic. Are there any closing comments from the agency?

DR. FARCHIONE: I just want to echo the thanks to the applicant and to the committee, and especially to the folks who participated in the open public hearing today for sharing their stories. Thank you.

[p. 425]

Adjournment

DR. NARENDRAN: Thank you. With that, we will now adjourn the meeting. (Whereupon, at 5:43 p.m., the meeting was adjourned.)